Secondary Acute Lymphoblastic Leukemia (sALL) Is Associated with a Distinct Group of Primary Cancers and Has Prognostic Impact

Background: Multiple, small retrospective studies have suggested that ALL can occur as a secondary cancer, but the diagnosis of sALL remains controversial. Furthermore, its clinical significance remains poorly defined. Using population based data, we examined a large, retrospective cohort of patients with sALL to determine the risk factors for and prognostic impact of sALL compared to ALL without preceding cancer.

Methods: Patients diagnosed with ALL during 1988-2012 were identified in the California Cancer Registry (CCR) (n=15,135). Cases were considered sALL if they were preceded by any other malignancy except primary acute leukemia, chronic myeloid leukemia, Burkitt leukemia/lymphoma, lymphoblastic lymphoma or non-hodgkin lymphoma, not otherwise specified. Non-menaloma skin cancer is not captured by CCR, and thus was not included considered a first malignancy. We determined standard incidence ratios (SIR) for sALL by comparing expected rates of ALL from the CCR to observed rates in patients with a previous malignancy. Hematologic malignancies and breast, thyroid and germ cell cancers were identified as potential high-risk patients in prior reports. SIRs for these tumors and for colorectal and prostate cancer, due to their frequency, were calculated. The effect of sALL, compared to primary ALL, on overall survival (OS) was estimated using Cox proportional hazards models accounting for age, sex, race, year of diagnosis, histology, neighborhood socioeconomic status (SES), marital status, and rural vs urban residence.

Results: Secondary ALL accounted for 3.7% (n=566) of patients diagnosed with ALL in the CCR. Compared to primary ALL, sALL was more common in females (43% vs 55%, p<0.0001), non-Hispanic Whites (37% vs 62.9% p<0.0001), older patients (21% over the age of 40 vs 87%), more likely to be diagnosed in 2008-2012 than before (23% vs 31%, p<0.0001) and in patients residing in the highest two quintiles of SES (17% vs 22% p=0.002 and 16% vs 27% p<0.0001, respectively). The most common first primary tumor sites among sALL patients were breast (14%), male genital system (10%), lymphoma (8%), and digestive system (6.7%). The primary tumor site was unknown in 30% of cases.

The SIRs of developing sALL are summarized in the Table. Of note, both men and women were more likely to develop ALL after a preceding malignancy than the background population, overall SIR 1.7 (95% CI 1.5 – 1.8), male SIR 1.4 (1.2 – 1.6), and female SIR 2.0 (1.8 – 2.4). While hematologic malignancies and endocrine/thyroid cancers increased the risk in men and women, germ cell tumors increased the risk of sALL only in men; expectedly breast cancer increased the risk only in women.

Compared to primary ALL, the adjusted hazard ratio (aHR) of death for patients with sALL was 1.07 (0.96-1.18, p=0.2). A second model considered type of prior malignancy to sALL: hematologic malignancies, solid tumors with statistically significant SIRs >1 (breast, thyroid, and germ cell), and other tumors. Compared to primary ALL, patients with sALL after a prior hematologic malignancy had a significantly increased risk of death (aHR 1.38, 1.07 – 1.8), while those with prior breast/thyroid/germ cell (aHR 1.18, 0.95 – 1.46) or any other primary (aHR 1.12, 0.96 – 1.31) cancers did not.

Conclusions: To our knowledge, this study represents the largest cohort of sALL reported to date, and establishes sALL as a clinically relevant subtype of ALL. Although the risk of developing sALL is increased for patients with any prior malignancy, only specific cancers provide excess risk. Furthermore, the risk of death was increased in sALL patients with a prior hematologic cancer. Our findings provide evidence that sALL is clinically distinct entity, and have implications for both survivorship of solid and hematologic cancer and risk stratification of ALL. Further study into the etiology of sALL, and the possibility that sALL is therapy related, is warranted.

Table: SIRs by Primary Site and Gender
	Total		Males		Females
Primary Site	SIR	95% CI	SIR	95% CI	SIR	95% CI
Any	1.7#	(1.5 – 1.8)	1.4#	(1.2 - 1.6)	2.0#	(1.8 - 2.4)
Solid tumor	1.4#	(1.3 - 1.6)	1.1	(0.9 - 1.3)	1.8#	(1.5 - 2.1)
Hem	5.5#	(4.3 – 7.0)	5.1#	(3.6 - 7.0)	6.1#	(4.1 - 8.7)
Breast	1.8#	(1.4 - 2.2)	0	(0 - 12.4)	1.8#	(1.4 - 2.3)
Colorectal	1.3	(0.8 - 1.8)	1.2	(0.6 - 1.9)	1.4	(0.4 - 2.4
Prostate	0.9	(0.7 - 1.2)	0.9	(0.7 - 1.2)	0	(0 - 0)
Endocrine/Thyroid	3.0#	(1.7 - 4.9)	3.9#	(1.4 - 8.4)	2.6#	(1.2 - 4.9)
Germ Cell	2.4#	(1.2 - 4.3)	3.6#	(1.5 – 7.0)	1.3	(0.3 - 3.8)
#: p<0.05